Agonists for G protein coupled receptors (GPCRs), including angiotensin II (Ang II) and catecholamines, play a key role in cardiac hypertrophy and heart failure in patients. GPCRs not only activate direct downstream targets ofheterotrimeric G proteins but also trans-activate other signaling mechanisms, including tyrosine kinases, in a heterotrimeric G protein independent manner. Our preliminary, studies suggest that the Ang II type I (AT1) receptor and the beta 1 adrenergic receptor (beta 1AR), the key GPCRs regulating hypertrophy and failure, utilize several novel signaling mechanisms including: 1) activation of Src tyrosine kinases by heterotrimeric G protein-independent mechanism 2) direct interaction between GPCRs and intracellular signaling molecules, and 3) activation of the endocytosis machinery-dependent signaling mechanisms. We have obtained evidence that these signaling mechanisms are involved in regulation of growth and death of cardiac myocytes. Our goal in this project is to elucidate the functional significance of these novel signaling events in growth and death of cardiac myocytes and to understand how GPCRs attain precise and specific control over growth and death of cardiac myocytes. We will address these issues by using unique reagents developed and transgenic animals in collaboration with PPG investigators. We propose: 1) To determine the specific role of heterotrimeric G protein-dependent and tyrosine kinase-dependent cell signaling in Ang II-induced cardiac hypertrophy.2) To determine the role of the amino acid-sequence specific interaction between AT 1 receptors and thioredoxin in Ang II-induced cardiac hypertrophy and apoptosis 3) To determine the role of the endocytosis machinery in cardiac hypertrophy and apoptosis by beta AR. Understanding the role of each signaling mechanism in GPCR-induced cardiac hypertrophy and apoptosis is extremely important, since this should explain the differences in cardiac phenotypes and prognosis in cardiac hypertrophy caused by distinct stimuli. Knowledge obtained from this study should allow-us to develop strategy to precisely control cardiac hypertrophy and apoptosis by eliminating undesirable phenotypes, and to delay the transition from cardiac hypertrophy to heart failure in the patients.